Healthy cell growth depends on the ability to properly repair DNA damage, but the outcomes of the DNA damage response can vary greatly. Some cells repair damage and continue growing normally, while other cells suffer apoptosis, senescence or become malignant cancer cells. The biological reasons for these differing responses are not always clear, but the consequences in terms of health (especially in aging and cancer) are profound. The goal of our research program is to show why different cells respond differently to stress, with the goal of reprogramming cells so that they repair damage in an advantageous way.

We previously showed that mutation and cancer arise in cells lacking the BRCA1 tumor suppressor gene, as a consequence of imprecise repair of DNA damage by the nonhomologous end-joining (NHEJ) pathway. By targeting specific repair factors in BRCA1-deficient cells, it is possible to prevent mutation, and select for healthy cell growth. We aim to build on this work to better understand differences between damage response pathways in different cell types. For example,

• Do stem cells react to damage differently from somatic cells? • What mechanisms regulate choice of DNA repair pathways? • Do damage responses affect the chromatin environment of the genome? • Is it possible to identify drugs or other treatments that bias cellular damage responses?

We study these questions in genetically-targeted mice using a variety of molecular and biochemical techniques. Specific projects underway in the lab include studying the importance of the BLM and Exo1 proteins in regulating how DNA double-strand breaks are processed. We are also using mouse models and structural biology approaches to test how the BRCA1 tumor suppressor functions at the molecular level. The importance of ubiquitylation in the DNA damage response is another theme, especially focusing on the activity of the SUMO-targeted ubiquitin ligase, RNF4. Finally, through our active partnership with colleagues at the Rutgers Cancer Institute of New Jersey, we are using data from whole-genome sequencing approaches to study how individual mutations in human cancer patients affect DNA repair.